2857-LB: Glycemic Improvements with Icovamenib in T2D on Background GLP-1 Therapy: COVALENT-111 Subgroup Analysis

Introduction and Objective: Many individuals with T2D remain inadequately controlled despite treatment with GLP-1 receptor agonists (RA). Icovamenib is an orally administered investigational small molecule for diabetes. Icovamenib targets menin, a transcriptional regulator implicated in beta-cell dysfunction, that modulates pathways regulating insulin secretion. COVALENT-111 evaluated icovamenib in adults with inadequately controlled T2D. This analysis assessed glycemic outcomes in those receiving background GLP-1 RA therapy at baseline. Methods: COVALENT-111 is a randomized, placebo-controlled study evaluating icovamenib in adults with T2D. Eligible participants had HbA1c 7.0-10.5% while receiving stable antihyperglycemic therapy. Participants continued baseline therapy and were randomly assigned to 100mg icovamenib or placebo once daily for 8-12 weeks. This subgroup analysis included participants receiving background GLP-1 RA therapy at baseline. The primary outcome was change in HbA1c. Safety was evaluated through adverse event monitoring. Results: 12 icovamenib- (age 53±9 yr, T2D duration 5.4±0.8 yr, HbA1c 8.4±0.9%, BMI 35.1±3.3 kg/m2, mean±SD) vs 4 placebo-treated (age 58±9 yr, T2D duration 4.8±2.6 yr, HbA1c 7.9±0.3%, BMI 32.5±3.5 kg/m2) patients. At Week 52, treatment with icovamenib resulted in mean HbA1c change of -1.2%, compared with +0.6% with placebo, corresponding to a placebo-adjusted reduction of 1.8% (p=0.05). C-peptide index improved relative to placebo. Icovamenib was generally well tolerated; no serious AEs or discontinuations. The safety profile in participants on background GLP-1 therapy was consistent with overall study population. Conclusion: In adults with T2D receiving background GLP-1 RA therapy, icovamenib showed clinically meaningful reductions in HbA1c vs placebo, with the benefit continuing at 52 weeks. These findings suggest icovamenib may provide additive glycemic benefit alongside GLP-1-based therapy and support further evaluation of menin inhibition for T2D. Disclosure J.P. Frias: Employee; Ended; Biomea Fusion.